Jbptitbche Gdl Publ 2003 Yasuhikohi 1 AAA221282 4

Applied Catalysis A: General 221 (2001) 197–207

Heterocyclic compounds such as pyrroles, pyridines, pyrollidins,piperdines, indoles, imidazol and pyrazins

Ya Suhiko Higasio∗, Takayuki ShojiYa Koei Chemical Company Ltd., 2-12-13 Hanaten-nishi Jyoko-ku Osaka, Japan

Abstract

Nitrogen-containing compounds are used as structural components of pharmaceuticals and agrochemicals due to their highbiological activities. There are many nitrogen-containing chemicals, from simple structured compounds as pyridine bases tocomplicated compounds as pharmaceutical ingredients and their number is growing rapidly year by year.

Among the nitrogen containing compounds, pyridine bases are produced in by far the largest quantity and are used invarious applications as herbicides, insecticides, vitamins like nicotinic acid and nicotinic acid amide, pharmaceuticals andadhesives. Pyrazines are used in flavors and fragrances and pharmaceutical intermediates. Among them, 2-methylpyrazineis used as a raw material of anti-tuberculosis drug, i.e. pyrazinamide. Pyrrole is used as a raw material of polypyrrole ratherthan in pharmaceutical applications. Polypyrrole has attracted much attention recently as an electroconductive polymer andits inexpensive production process is required.

This article describes about such fundamental nitrogen-containing heterocyclic compounds as pyridine bases, pyrazines,piperidine, pyrrolydine, pyrrole, indole and imidazole. © 2001 Published by Elsevier Science B.V.

Keywords: Heterocyclic compounds; Pyrazine; Polypyrrole

1. Pyridine bases

Pyridine bases were isolated from coal tar in 1846by Anderson [1]. Compounds containing a pyridinering, such as Vitamin B, nicotinamide, and nicotinicacid, play important roles in metabolism. Pyridinebases were isolated from coal tar before synthetic man-ufacturing processes established (Fig. 1).

1.1. Production

1.1.1. Synthesis of 5-ethyl-2-methylpyridine frompara-aldehyde and ammonia

Reaction ofpara-aldehyde with aqueous ammoniain the liquid-phase is carried out in the presence of

∗ Tel.: +81-6-6961-0164; fax:+81-6-6961-0206.E-mail addresses: [email protected] (Y. Higasio),[email protected] (T. Shoji).

an ammonium salt to give 5-ethyl-2-methylpyridine(MEP) [2,3] (Figs. 2 and 3).

Process: (a)para-aldehyde production; (b) pyridinereactor; (c) separator; (d) stripper; (e) dewatering col-umn; (f) fractionating columns.

1.1.2. Synthesis from aldehydes or ketones withammonia

The reaction of aldehydes or ketones with am-monia is the most general synthetic reaction forthe manufacture of pyridine bases and allows thepreparation of various pyridine bases. This re-action was first studied in detail by Chichibabinin 1924 and since then been studied extensivelyfor industrial manufacturing because of inex-pensive access to raw materials [4] (Figs. 4–6;Tables 1–4).

0926-860X/01/$ – see front matter © 2001 Published by Elsevier Science B.V.PII: S0926-860X(01)00815-8

198 Y.S. Higasio, T. Shoji / Applied Catalysis A: General 221 (2001) 197–207

Fig. 1. Pyridine bases.

Fig. 2. Mechanism of 5-ethyl-2-methylpyridine formation.

Y.S. Higasio, T. Shoji / Applied Catalysis A: General 221 (2001) 197–207 199

Fig. 3. Flow sheet of 5-ethyl-2-methylpyridine production by Montecatini–Edison process.

1.1.3. Synthesis from acrylonitrile and ketonesSynthesis from acrylonitrile and ketones is

one of the current processes for manufacturing2-methylpyridine. This process gives 2-methylpyridineselectively, in contrast to the process using acetalde-hyde and ammonia, which gives 4-methylpyridine asa byproduct. First, the reaction of acrylonitrile andacetone, catalyzed by a primary aliphatic amine, oc-

Fig. 4. Flow sheet of pyridine and methylpyridine production from acetaldehyde and formaldehyde with ammonia. (a) reactor; (b) collector;(c) extraction; (d) solvent distillation; (e) distillation.

curs in the liquid-phase to give 5-oxohexanenitrile.The cyclization and dehydration of the initial prod-uct are carried out in the gas-phase in the pres-ence of hydrogen over a palladium, nickel, orcobalt-containing catalyst to give 2-methylpyridine[16]. 4-Methyl-5-oxohexanenitrile, formed from acry-lonitrile and 2-butanone, gives 2,3-dimethyl-pyridine[17] (Fig. 7).


Fig. 5.

Fig. 6.

1.1.4. Synthesis from dinitrilesIn the vapor-phase reaction over a nickel-containing

catalyst in the presence of hydrogen, 2-methylgluta-ronitorile gives 3-methylpiperidine, which then under-goes dehydrogenation over palladium-alumina to give3-methylpyridine [18–21] (Fig. 8).

Table 1Synthesis from aldehydes or ketones with ammonia

Material Product

Acetaldehyde 2-Metylpyridine, 4-methylpyridinAcetoaldehyde,

formaldehydePyridine, 3-methylpyridine

Acrolein 3-MethylpyridineAcrolein, acetoaldehyde PyridineAcetone, formaldehyde 2,6-DimethylpyridineAcrolein, propionaldehyde 3-MethylpyridineAcrolein, acetone 2-MethylpyridinePropionaldehyde,

formaldehyde3,5-Dimethylpyridine

Table 2Synthesis of 2- and 4-methylpyridine from acetaldehyde and am-monia

Company Catalyst References

Koei Chemical Co. Co3Al3(PO4)5− [5]Nihon Kayaku Co. Al2O3-SiO2-CdCl2 [6]

Table 3Synthesis of 3-methylpyridine and pyridine from acrolein andammonia


Degussa Co. Al2O3-MgF2 [7]ICI Co. SiO2-Al2O3-H2SiF2 [8]Nihon Kayaku Co. SiO2-Al2O3-CdF2 [9]Koei Chemical Co. SiO2-Al2O3-MnF2 [10]Daicel Chemical Co. SiO2-Al2O3 [11]


Table 4Synthesis of pyridine and 3-methylpyridine from acetaldehyde andformaldehyde with ammonia


ICI Co. SiO2-Al2O3 coke [12]Rutgerswerk Co. SiO2-Al2O3 CdF2 [13]Nepera Co. ZSM-5 [14]Koei Chemical Co. Tl-ZSM-5 [15]

1.1.5. Dealkylation of alkylpyridinesAlkylpyridines of low commercial value, obtained

as byproducts of pyridine base synthesis, are occasion-ally converted into useful pyridine bases by dealkyla-tion. The methods for dealkylation involve oxidativedealkylation by air over a vanadium oxide catalyst [8],steam dealkylation over a nickel catalyst [9,10] andhydrodealkylation over a silver or platinum catalyst[22].

1.1.6. Synthesis from nitriles and acetyleneLiquid-phase reaction of nitriles with acetylene is

carried out in the presence of an organocobalt catalystto give 2-substituted pyridines [23] (Fig. 9).

1.1.7. Separation from tarPyridine bases are constituents of tars. They were

isolated from coal tar or coal gas before syntheticmanufacturing processes became established. The

Fig. 7.

Fig. 8.

Fig. 9.

amounts contained in coal tar and coal gas are small,and the pyridine bases isolated from them are mixtureof many components. Thus, with a few exceptions,isolation of pure pyridine bases was expensive. Today,almost all pyridine bases are produced by chemicalsynthesis.

1.2. Uses

1.2.1. PyridinePyridine is an excellent solvent, especially for de-

hydrochlorination reactions and extraction of antibi-otics. A large amount of pyridine is used as a startingmaterial for pharmaceuticals and agrochemicals.

1.2.2. 2-MethylpyridineThe major use of 2-methylpyridine is a precursor

of 2-vinylpyridine. The terpolymer of 2-vinylpyridine,butadiene and styrene is used as an adhesive for textiletire cord. 2-Methylpyridine is also used as material fora variety of pharmaceuticals and agrochemicals.


1.2.3. 3-MethylpyridineA considerable amount of 3-methylpyridine is used

as a starting material for pharmaceuticals and agro-chemicals: for example, feed additives such as nico-tinic acid and nicotine carboxamide.

1.2.4. 4-MethylpyridineThe primary use of 4-methylpyridine is in the

production of anti-tuberculosis agent isonicotinichydrazide. Polymers containing 4-vinylpyridine, ob-tained from 4-methylpyridine, are used as anionexchangers.

1.2.5. PolyalkylpridinesA large amount of MEP is used as starting mate-

rial for nicotinic acid. Dimethylpyridines are used forpharmaceuticals and agrochemicals.

2. Pyrazines

Pyrazines play an important role as intermediatesfor perfumes, pharmaceuticals and agricultural chemi-cals. Especially, amides and sulfonamides of pyrazineshave been used on various topics as anti-tuberculosis,oral anti-diabetics, nutrition supplement, insecticidesand fungicides.

Okada found, for the first time, that pyrazinecompounds can be produced by the catalytic re-action of diamines with diols in a vapor-phase re-

Table 5

Reaction Company Catalysts References

Koei Chemical Co. Cu-Cr2O3 [29]

BASF A.-G. Pd-MgCl2-Al2O3 [30]

Wyandotte Chemical Co. Cu-Cr2O3 [31]

Hasegawa T. Co. Cu-Cr2O3 [32]

Fig. 10.

action in the presence of granular alumina [24].Catalytic systems such as copper-chromium [25],copper-zinc-chromium [26], zinc-phosphoric acid-manganese [27] and silver [28] are also patented ascatalysts for preparation of 2-methylpyrazine (MP)from ethylene diamine (ED) and propylene glycol(PG) (Fig. 10).

It is also possible to obtain pyrazines fromcondensation reaction of diamines and epoxides, con-densation reaction between alkanolamines or cyclode-hydrogenation ofN-(-hydroxyalkyl)alkyl diamine onthe same catalysts. In the presence of copper-zinccatalysts, dehydrogenation of piperazines give corre-sponding pyrazines with high yield (Table 5).

Formi et al. studied the mechanism of the cycliza-tion of ED and PG to give MP on zinc-chromium cat-alyst by means of TPD-TPR-MS technique [33]. Theypropose a mechanism which involves an intermedi-ate (methylpyperazine) formation between adsorbedPG and gaseous ED which in turn carry out dehy-drogenation and aromatization to give methylpyrazinebecause adsorbed ethylene oxide was not observed(Fig. 11).


Fig. 11.

Fig. 12.

On the other hand, in the liquid-phase reaction,Nippon Soda Co. established an industrial manufac-turing process for the preparation of pyrazines fromdiaminomaleonitrile (DAMN) [34]. Tetramerizationof hydrogen cyanide yields DAMN. Pyrazines areproduced from DAMN and glyoxals in the presenceof oxalic acid. These cyano-substituted pyrazines playimportant roles as industrial intermediates becausethey are easily functionalized to amino, carboxyl oramide group (Fig. 12).

3. Piperidine

Piperidine is the alicyclic compound containing anitrogen. Piperidine is used as a raw material for phar-maceuticals, agrochemicals, rubber chemicals, surfaceactive agents and other organic chemicals.

Piperidine is commonly manufactured by hydro-genation of pyridine over Pt, Pd or Raney-Ni [35] cat-

Fig. 13.

alyst in the liquid-phase reaction (Fig. 13). The reduc-tion with sodium and alcohol is also reported.

Piperidine is also manufactured by cyclizationof aliphatic compounds such as 1,5-pentanediol[36], 5-amino-1-pentanol [37], 1,5-pentanediamine[38] and glutaronitrile [39]. These reactions are notonly carried out in the liquid-phase but also in thevapor-phase as shown in equation (Figs. 14 and 15).

Synthesis of piperidine from furfural is reported toinvolve following three steps of reaction: synthesis offurfurylamine by hydrogenating ammonolysis of fur-fural, synthesis of tetrahydrofurfurylamine (THFFA)


Fig. 14.

Fig. 15.

Fig. 16.

Fig. 17.

by hydrogenation of furan ring and preparation ofpiperidine by selective hydrogenolysis of THFFA[40]. First two steps can be carried out over the samecobalt catalyst and the third step is carried out byanother cobalt catalyst at high yield. The third stepreaction is carried out by continuously removing theproduct piperidine to the vapor-phase to minimizethe side reaction, thus achieving high yield (Figs. 16and 17).

Other than those reactions mentioned above, manyreports have described the synthesis of piperidine

Fig. 18.

by reduction of substituents such as in the case ofN-nitrosopiperidine and -piperidone (Fig. 18).

4. Pyrrolidine

Pyrrolidine is a strongly basic (K25 = 1.3 × 10−3)liquid secondary amine which is found in tobaccoleaves with strong piperidine like odor. Its derivativesare used in pharmaceuticals, especially as modifiersof quinolone anti-bacterial agents. It is also used as araw material of vulcanization accelerator.

The production processes of pyrrolidines are: (1)transformation ofO-heterocycles toN-heterocyclesby reaction of tetrahydrofuran with ammonia orprimary amines, (2) cyclization of 1,4-butanediol,1,4-diaminobutane or 1,4-dicyanobutane (succinoni-trile) and (3) reduction of pyrroles. The method (2)has been adopted in the industrial applications.

Pyrrolidine is obtained in high yield by the vapor-phase reaction of tetrahydrofuran and ammonia overH-ZSM-5-type zeolite or alumina-silica catalyst[41,42]. Ono et al. studied the reaction mechanismextensively using Y-zeolite [43].

Pyrrolidine is easily obtained by catalytic vapor-phase reaction of 1,4-butanediol and ammonia overactive alumina [44]. It is also reported that the yieldof the same reaction was improved at higher pres-sure. Pyrrolidine is also obtained by the cyclization of1,4-diaminobutane using phosphorous(V)oxide-typecatalyst [45]. In the liquid-phase reaction, Pyrrolidineis obtained by the reduction of succinonitrile in liquidammonia with Raney-Ni catalyst [46]. The hydro-genation of pyrrole over Raney-Ni in ethanol alsogives pyrrolidine [47] (Fig. 19).

5. Pyrrole

Pyrrole (1H-pyrrole, azole) is a five-member het-erocyclic compound and is biochemically importantmaterial which is found in hem, chlorophyll and many


Fig. 19.

Fig. 20.

alkaloid structures. It is also used in electric/electronicapplications because of the high electroconductivityof its polymer (polypyrrole).

Pyrrole can be isolated from coal tar or bone oil. Itis also obtained by zinc-acetic acid reduction of suc-cinimide. However, these methods are not recognizedas industrial manufacturing method because of the lowcontent in the raw material or low selectivity reactionwith many byproducts.

There are two industrial production methods of pyr-role. They are: (1) the reaction of furan with ammonia[48], and (2) dehydrogenation of pyrrolidine [49]. Theformer method is the reaction of furan with ammoniaover alumina or silica-alumina at 450–500◦C to givepyrrole at 50–60% yield [48]. Either method is anefficient method to obtain pyrrole in a commercialscale (Fig. 20).

Fig. 21.

6. Indole

Indole is a heterocyclic compound with fused struc-ture of benzene ring with pyrrole ring. Indole was dis-covered by A.V. Baeyer and C.A. Knop in 1866 asthe basic structure of the natural dye, indigo, fromwhich it was obtained. In 1910, R. Weissgerber foundindole, in coal tar. It is a colorless clear solid withm.p. 52–54◦C and b.p. 254.7◦C. It is readily solublein most solvents like ethanol, diethyl ether and ben-zene, soluble in hot water, slightly soluble in cold wa-ter and volatile in steam.

Because of its natural source, as a component ofjasmine oil and orange flower oil, indole has been usedfor many years to fix fragrances and is therefore foundin many perfumes. A further important application isthe production of the amino acid tryptophan.

High-temperature coal tar, contains in average justunder 0.2% of indole. Good portion of Commercialmaterial is obtained from coal tar. In addition to theisolation from coal tar, indole is also synthesized incommercial quantities.N-hydroxyethylaniline, whichcan be produced from aniline and ethylene oxide,can be converted at 325 on SiO2 [50] or Pd/C [51].O-Hydroxyethylaniline can be converted to indole inthe presence of RuCl2(PPh3)3 in the liquid-phase [52].In recent years, the cyclocondensation of aniline withethylene glycol on Ag/SiO2 catalysts gives indole in69% yield at 400 in a hydrogen atmosphere [53]. Inthe liquid-phase, reaction of aniline with ethylene gly-col in the presence of SiO2-CuO-MgO gives indole at75.5% yield [54] (Fig. 21).

7. Imidazole

Imidazole is a highly valuable intermediate for theproduction of pharmaceuticals and agrochemicals. It is


Fig. 22. Liquid-phase.

Fig. 23. Vapor-phase.

Fig. 24.

used as a curing agent for epoxy resins and an anti-rustagent. Recently, it became an industrially importantintermediate in the area of photo-sensitive or heat sen-sitive applications.

The main production process employs a reactionof glyoxal with formaldehyde and ammonia overRaney-Ni catalyst. The reaction is carried out in theliquid-phase between 50 and 100 and high purity im-idazole is obtained after rectification of the reactionmixture [55]. Substituted imidazoles may be obtainedby altering the substituents of starting glyoxal, alde-hyde and amine (Fig. 22).

Imidazole is also produced in the vapor-phase reac-tion from formamide, ethylenediamine and hydrogenover platinum on alumina between 340 and 480 [56](Fig. 23).

N-substituted imidazole is formed by the reactionof amines instead of ammonia in the liquid-phase.2-Methylimidazole is synthesized from glyoxal andacetaldehyde with ammonia [55]. 2-Methylimidazolecan also be prepared from ethylenediamine and ace-tonitrile in the presence of sulfur (Fig. 24).

The production processes of imidazoles have beenstudied extensively in recent years and many patentshave been applied in this field.

8. Conclusions

Generally speaking, production of a certain chem-ical compound may be achieved in an unexpectedlyshort process in vapor-phase reactions compared withliquid-phase reactions. However, the plant construc-tion cost is usually higher in vapor-phase reaction thanin liquid-phase reaction. Majority of nitrogen contain-ing pharmaceutical or agrochemical intermediates areproduced in tens of metric tons to hundreds of metrictons per year with a few exception of pyridine bases inagrochemical applications which require several thou-sand to tens of thousand metric tons per year of thematerial. Thus, vapor-phase reaction is sometimes dif-ficult to apply for the small quantity production of spe-cialty chemicals. In order for the use of vapor-phasereaction, construction of multi-purpose plant with a ca-pability to produce multiple products with short downtime in product change and the strategic selection ofproducts which are suitable for the optimum operationof the plant should be necessary.

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Jbptitbche Gdl Publ 2003 Yasuhikohi 1 AAA221282 4